ABSTRACT
Biliary tract cancer (BTC) is a series of rare malignancies with poor overall prognosis. Radical surgery the preferred treatment option, but most patients have lost the opportunity of surgery at the time of diagnosis. At present, there are limited systematical treatment options for biliary tract cancers, and such treatments have poor efficacy and short duration of responses. In the past few years, immune checkpoint inhibitor therapy has been established as an effective systemic therapy option for many solid tumors and hematological tumors. The research for biliary tract cancer treated by of immune checkpoint inhibitors has been continuously carried out and demonstrated the anti-tumor efficacy and safety. However, in view of the low incidence and high heterogeneity of BTC more large number of clinical trials and practices need to be carried out, and the effective combination regimens and predictive biomarkers are urgent to be explored. This article reviews the recent clinical studies on immune checkpoint inhibitors for biliary tract cancer, and summarizes the ongoing clinical studies. At the same time, the predictive biomarkers of immune checkpoint inhibitors proposed by domestic and foreign researches in recent years are summarized.
ABSTRACT
Biliary tract cancers are group of highly heterogeneous malignant tumors derived from gallbladder and bile duct epithelium， including gallbladder cancer and cholangiocarcinoma， with a high degree of malignancy. When diagnosed， the course of disease often develops to the middle and late stage， with a poor prognosis. It is difficult to treat the advanced biliary tract cancers， with a lack of unified chemotherapy standard and targeted drugs. Traditional Chinese medicine（TCM） compound has multi-target， multi-link and multi-path characteristics， with effects in stabilizing tumor， alleviating clinical symptoms， alleviating side effect of radiotherapy and chemotherapy， and improving the quality of life. Especially in the treatment of advanced cancer patients， it plays an irreplaceable role. Therefore， it is concerned by many researchers. According to TCM， the pathogenesis of patients with advanced biliary tract cancers are mainly due to asthenia of healthy Qi and sthenia of pathogenic factors， Yin-Yang disharmony， and simultaneous occurrence of cold and heat. The location of the disease is related to liver， gallbladder， spleen， stomach and kidney. Because the advanced biliary tract cancers are similar to Jueyin syndrome in disease location， course and disease， Wumeiwan is often used in clinical treatment. Based on "theory， method， prescription and medicine" of TCM， Wumeiwan has the effect in regulating cold and heat， clearing the upper and lower temperature， warming the liver and supporting Yang， attacking and supplementing simultaneously， balancing the liver， spleen and kidney， which conforms to the TCM syndrome characteristics of advanced biliary tract cancers， according to modern Chinese medicine pharmacology， many effective ingredients in Wumeiwan have the effects in inducing tumor cell apoptosis， inhibiting tumor cell proliferation and reducing tumor cell proliferation， reducing inflammatory response in the body， inhibiting angiogenesis， reversing multidrug resistance of tumor cells and regulating immunity. This paper analyzes the feasibility of treatment of advanced biliary tract cancers with Wumeiwan from the perspective of traditional Chinese and Western medicine， so as to provide reference for clinical comprehensive treatment of advanced biliary tract cancers and the experimental study of TCM.
ABSTRACT
Objective:To explore the impacts of postoperative radiotherapy on long-term survival of the patients with resectable locally advanced (T 3-4and/or N +) biliary tract cancers (BTCs) and to analyze the prognostic factors. Methods:The patients with locally advanced gallbladder cancer ( n=1 922) and the patients with extrahepatic biliary duct cancer ( n=3 408) who received surgical resection during 2006-2016 were selected from the Surveillance, Epidemiology, and End Result (SEER) database. They were grouped according to different treatment schemes (only surgery and surgery + radiation). The propensity score matching (PSM) method was employed to adjust the differences in baseline prognostic characteristics between patients who received only surgery and those treated with surgery+ radiation. The role of the two treatment schemes on the survival of the patients was analyzed using the Kaplan-Meier method and the prognosis factors were assessed using the Cox regression. Results:The 1 174 patients with gallbladder cancers and the 2 144 patients with extrahepatic biliary duct cancer were respectively matched according to propensity scores. The postoperative radiotherapy showed a significant advantage in 5-year cancer-specific survival (CSS) compared to only surgery for both the patients with gallbladder cancer ( χ2=35.73, P< 0.001) and those with extrahepatic biliary duct cancer ( χ2=9.878, P=0.002). After adjusting related covariates, independent prognostic factors for all the patients included pathological grading, T status, N status, treatment pattern, and age. For the patients with extrahepatic biliary duct cancer, independent prognostic factors also included race and year of diagnosis. The benefits of postoperative radiotherapy were observed in various clinicopathologic characteristics except for the patients with T 1-2 gallbladder cancer and the extrahepatic biliary duct cancer patients with a pathological grade of Ⅰ-Ⅱ and N 0 status or with age ≥ 70. Conclusions:Long-term survival benefits can be gained through postoperative radiotherapy for the patients with resectable locally advanced (T 3-4 and/or N+ ) BTCs. However, adjuvant radiation should be cautiously adopted for the patients with T 1-2 gallbladder cancer and the extrahepatic biliary duct cancer patients with a pathological grade of I-Ⅱ and N 0 status or with age ≥70.
ABSTRACT
This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR T cell 2.1 × 10/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.